tbuckley/cabot-search huggingface dataset:
Immune-related adrenal insufficiency: A single center retrospective analysis.
Authors: Natalya Polshina, Daria Filonenko, Ekaterina Volkova, Lyudmila Zhukova
Journal: Journal of Clinical Oncology (2023)

2659 Background: Immune checkpoint inhibitors (ICI) became widely used for treatment of various malignancies. They may cause different immune-related adverse events (irAEs), including adrenal insufficiency (irAI). IrAI was reported to be comparatively uncommon but potentially life threatening. We conducted a retrospective single center study to identify and describe the incidence and characteristics of AI associated with ICI. Methods: We reviewed the medical records of patients treated at an oncological department at Loginov Moscow Clinical Scientific Center between Sep’2019 and Jan’2023 with immunotherapy under direct cortisol monitoring every 6-8 weeks. The main criteria for AI was low serum cortisol in the absence of glucocorticoid intake. Results: A total 101 patients (pts) treated by ICI or ICI in combination with chemotherapy or targeted therapy for various malignancies were included in our retrospective analysis. 16 patients (15.8%) were diagnosed with AI: 7 pts with renal cell carcinoma (RCC), 6 pts with melanoma (2 in adjuvant setting), 1 with non-small-cell lung cancer (NSCLC), 1 with small-cell lung cancer (SCLC), 1 with MSI-high colorectal cancer (CRC). Median age was 65 (range 46-79), the majority (10 pts, 62.5%) were male. The median time of irAI onset from ICI start was 5 months (range 2-15). Assessment of serum cortisol was performed every 6-8 weeks routinely and off-schedule in patients who had new onset AI-like symptoms. The most frequent symptoms were unspecific and included fatigue and weakness (100%), loss of appetite/anorexia (69%), hypotension (50%), weight loss (44%), insomnia (38%), chills (31%), nausea/vomiting (31%), muscle pain or cramps (31% and 25% respectively), dizziness (25%), dry mouth (25%), headache (13%), fever (6%). Remarkably, laboratory detected serum cortisol decline preceded any AI symptoms in 7 patients (43.7%). Other 7 patients (43.7%) had concurrent secondary hypothyroidism which suggested panhypopituitarism. Hydrocortisone replacement led to rapid symptoms recovery in 15/16 patients. Additional treatment with fludrocortisone was required for only one patient who had primary/mixed AI due to bilateral metastases of RCC in adrenal glands. All patients resumed immunotherapy after symptoms resolved. Only 1 patient needed treatment modification (ipilimumab cessation). By 12th February 2023 median follow-up from irAI onset is 7 months (range 0.5-37), 12 patients are alive, they all remain on permanent hydrocortisone replacement therapy. Conclusions: Routine cortisol assessment during immunotherapy allowed us to detect irAI in 15.8% of patents that is higher than usually reported. Detection of irAI before clinical presentation let us prevent severe consequences including life threating. We consider that routine cortisol assessment during immunotherapy should be implemented in clinical practice.
FDA analysis of treatment-free survival in frontline advanced immuno-oncology–VEGF TKI renal cell carcinoma trials.
Authors: Elaine Chang, Jiaxi Zhou, Chi Song, Haley Gittleman, Laura L. Fernandes, Chana Weinstock, Michael B. Atkins, Sundeep Agrawal, Rajeshwari Sridhara, Nicole Gormley, Laleh Amiri-Kordestani, Shenghui Tang, Paul Kluetz, Daniel L. Suzman, Richard Pazdur, Brian I. Rini, David F. McDermott, Meredith M. Regan
Journal: Journal of Clinical Oncology (2023)

e13602 Background: Treatment-free survival (TFS) with and without (w/o) toxicity are outcome measures that describe health states where patients are experiencing clinically stable disease while off anti-cancer treatment, a clinically meaningful attribute seen with some immune-oncology (IO) regimens. We sought to characterize TFS with and w/o ongoing toxicity in addition to time on protocol therapy (combination and monotherapy) in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in pts with advanced renal cell carcinoma (aRCC). Methods: We pooled randomized trials submitted to FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months (mos) of median follow-up. OS was partitioned into health states, including TFS, defined as area between Kaplan-Meier curves for 2 time-to-event endpoints originating at randomization: 1) time to all protocol therapy cessation and 2) time to subsequent systemic therapy initiation or death. Health state areas under the curve were estimated by 30-mo restricted mean times. We pooled data by treatment arm. Results: Three trials (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER) met criteria for analysis; in total, 1183 pts received IO-TKI vs. 1184 on control arms receiving sunitinib (SUN). IO-TKI and SUN groups spent 9% (2.7 mos [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 mos [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free. Mean TFS with grade ≥3 toxicity were 1 and 0.6 mos in the IO-TKI and SUN groups, respectively. Mean TFS w/o grade ≥3 toxicity were 1.7 and 2.3 mos in IO-TKI and SUN groups, respectively. In IO-TKI group, the 30-mo mean time on combination therapy was 13.7 mos (46% of 30-mo period) and 3.9 mos on monotherapy (13% of 30-mo period). Following cessation of one drug in IO-TKI arm, monotherapy duration of TKI was longer than IO: 2.9 and 1 mos, respectively. Conclusions: In this descriptive, exploratory analysis, TFS and TFS w/o toxicity were similar in IO-TKI group compared to SUN group, in contrast to improved TFS in IO-IO vs. SUN seen in published literature. Among pts on IO-TKI, more time was spent on TKI monotherapy than IO monotherapy. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials, and may inform individual pt choice of IO-IO vs. IO-TKI. [Table: see text]
Immune-related hypophysitis: An analysis of a heterogeneous entity.
Authors: Abdel Rahman Nanah, Fatima Abdeljaleel, Olisaemeka Ogbue, Serhan Unlu, Sharmeen Sorathia, Hamed Daw
Journal: Journal of Clinical Oncology (2023)

e14704 Background: Immune-checkpoint inhibitors (ICIs) have led to revolutionary breakthroughs in the management of many malignancies. With the increasing use of ICIs, immune-related adverse events (irAE) have emerged and led to significant challenges and limitations. Immune-related hypophysitis, a potentially life-threatening irAE, has limited data on its diagnosis, clinical findings, and management. This was our incentive to characterize our single-institution experience with immune-related hypophysitis over the past 5 years. Methods: We retrospectively studied a cohort of adult patients who received ICIs at the Cleveland Clinic Foundation between 2017-2022. Our search was done by utilizing an outpatient oncology pharmacy database. Analyzed ICIs included atezolizumab, nivolumab, pembrolizumab, ipilimumab, avelumab, and durvalumab. The occurrence of immune-related hypophysitis was as determined by an endocrinologist or oncologist. Results: 6,615 patients received ICIs from 2017-2022, of which 27 patients were diagnosed with hypophysitis. Immune-related hypophysitis occurred with ICI monotherapy in 44.4% and combined therapy (ipilimumab and nivolumab) in 55.5%. The most commonly implicated agents were ipilimumab (74%), followed by nivolumab (59.3%), pembrolizumab (18.5%), and durvalumab (3.7%). In patients receiving ipilimumab-nivolumab, hypophysitis was detected after a median duration of 65 days (range: 29-163 days) from ICI initiation, compared to 58 days (38-112) with ipilimumab alone and 155 days (8-294) with pembrolizumab. Hypophysitis was grade 1 in 18.5%, grade 2 in 29.6%, grade 3 in 37%, and grade 4 in 14.8% of all patients. No hypophysitis-related deaths occurred. Signs and symptoms included constitutional symptoms (fever, anorexia, myalgia) in 88.89%, severe/intractable headaches in 40.7%, gastrointestinal complaints in 29.6%, dermatologic findings in 7.4%, visual symptoms in 7.4%, and syncope in 3.7% of all patients. Lab findings included abnormalities of TSH in 77.78%, ACTH in 70.60%, FSH and/or LH in 52.63%, and a positive ACTH stimulation test in 69.3%. Imaging findings were present in 62.5% of patients, and most commonly revealed pituitary gland enlargement, enhancement, or stalk thickening on brain/pituitary MRI. Treatment included glucocorticoid replacement in 92.6%, thyroid replacement in 40.7%, and testosterone in 7.4% of patients. All patients remained on glucocorticoid therapy indefinitely after hypophysitis was diagnosed. ICIs were momentarily held in 22.2% and discontinued in 51.86% of patients, while 25.9% of patients did not experience treatment interruptions. Conclusions: Immune-related hypophysitis is an uncommon irAE that presents with variable clinical and diagnostic findings. Nonetheless it is a cause of permanent glucocorticoid dependence. Healthcare professionals should be aware of this entity so treatment can be promptly started.
Effect of a novel expansion process on tumor-infiltrating lymphocyte (TIL) polyfunctionality, cytotoxicity, and expansion, while preserving cells in a less differentiated and more stem-like phenotype.
Authors: Andrew Yuhas, Joe Dean, Tim Erickson, Marcus Machin, Mohammed Alkhouli, Joe Yglesias, Rafael Cubas
Journal: Journal of Clinical Oncology (2023)

2542 Background: Adoptive cell therapy using autologous TIL has shown durable responses in patients with metastatic melanoma and some epithelial tumors (Chesney JITC 2022; Schoenfeld SITC 2021; O’Malley SITC 2021). Data suggest that maintaining a higher proportion of less differentiated and more stem-like TIL can associate with persistence and response in patients with metastatic melanoma (Krishna Science 2020; Rosenberg Clin Cancer Res 2011). Here, we describe a novel TIL expansion process that increases TIL expansion and preserves cells in a less-differentiated and more stem-like phenotype with enhanced functional output. Methods: Tumors of various histologies, including lung, breast, and renal cancer, were fragmented and expanded using either a standard process or a newly developed process that uses a different combination of cytokines during the pre-rapid expansion protocol (pre-REP) stage and another combination of cytokines and a pathway inhibitor during the REP stage to control T-cell activation and differentiation. The expansion potential, viability, and phenotypic and functional attributes of the final TIL products were evaluated by a variety of assays. Results: When compared with standard TIL expansion, the novel process increased yield and viability while preserving TIL in a less differentiated and more functional state, as evidenced by increased expression of the memory-associated markers CD27, CD28, CD62L, and IL-7R, with reduced expression of the activation markers CD38, CD39, and CD69, and lower levels of the inhibitory markers LAG3, TIM3, TIGIT, and TOX. Importantly, the novel process led to a pronounced increase in the tumor-homing marker CXCR3 as well as TIL polyfunctionality as evidenced by increased co-expression of IFNγ, TNFα, and IL-2 while showing an enrichment in genes associated with stem-like cells and a reduction in exhaustion-associated genes. Pseudotime trajectory analysis also demonstrated that the new expansion process maintained TIL in a less differentiated and more stem-like state. Together, these phenotypic and functional characteristics translated into increased cytotoxicity even after repeated stimulation. Conclusions: Our novel TIL expansion process improves multiple metrics that correlate with both TIL persistence and response, including enhanced polyfunctionality, reduced inhibitory receptor expression and a less differentiated and more stem-like phenotype, while increasing yield. These effects may translate into a more vigorous and less differentiated TIL infusion product with improved cytotoxicity and persistence.
Incidence of thromboembolic events in glioblastoma multiforme: The first Middle Eastern study risk stratifying patients from this region.
Authors: Mona Hassan, Antoine Nafez Finianos, Georges El Hasbani
Journal: Journal of Clinical Oncology (2023)

e14044 Background: Prophylactic anticoagulation for Glioblastoma Multiforme patients remains an area of high controversy with no definite guidelines and with clinical practice recommendations depending mainly on individual center based strategies. Considering that the middle eastern population is known to be associated with increased incidence of thrombophilia due to the high prevalence of factor V R506Q Mutation-Leiden and with no studies reporting incidence of VTE with GBM patients in this region, we aimed to conduct the first middle east based study to see if the incidence of VTE in GBM patient will be higher than the other overall reported incidence worldwide and we looked whether using the Khorana score will be a good predictor for assessing the need for VTE prophylaxis in these patients. Methods: we conducted a retrospective chart review to determine the incidence of initial VTE in GBM patients who received treatment at a tertiary care center in Beirut. Results: The total patient population was 132 with males constituting 71.2% of our population compared to 28.8 % females. Preexisting risk factors included: 34.8 % for hypertension, 65.2% for diabetes, and 25% were smokers, 0.8% had history of thrombophilia, and 7.6% had preexisting episode of VTE while 94% of the population had craniotomy. The incidence of deep vein thrombosis (DVT) was 15.4%, while 7.2 % developed a pulmonary embolism (PE). Recurrent VTEs affected 34.8% of those who had a previous VTE, and 7.4% of patients had the recurrent VTE while they were on anticoagulation. Regarding complications, 7.3% developed bleeding, 66% of those had intracranial bleeding while 33 % had a gastrointestinal bleed. Out of all of those who developed bleeding, only 3.4% were on anticoagulation so anticoagulation was not a major risk factor for bleeding. 57.6% of the patients had a Khorana score of 0, 28.8% had a score of 1,7.6% had a score of 2,1.6% had a score of 3, while 8% had a Khorana score of 4. In our cohort, all patients with a Khorana score of 3 and 4 developed VTE which indicated that this could be used as a risk assessment tool for our GBM patients. Conclusions: In conclusion in our study, with its retrospective limitation, we could not prove that our middle eastern populations, though known to have higher incidence of congenital thrombophilia, is associated with much higher incidence of VTE when compared to many studies involving different populations in the world however our cohort of patients with GBM undergoing craniotomy are still at increased risk of thrombotic events with low risk of bleeding despite anticoagulation and the Khorana score could be a risk stratifying method to help us establish the patients who have the highest risk of developing VTE. Prospective studies involving higher number of patients with thrombophilia testing should be explored to risk stratify our patients.
Generating synthetic samples of chondrosarcoma histopathology with a denoising diffusion probabilistic model.
Authors: Logan Nye, Hamid Ghaednia, Joseph H. Schwab
Journal: Journal of Clinical Oncology (2023)

e13592 Background: The emergence of digital pathology — an image-based environment for the acquisition, management and interpretation of pathology information supported by computational techniques for data extraction and analysis — is changing the pathology ecosystem. The development of machine-learning approaches for the extraction of information from image data, allows for tissue interrogation in a way that was not previously possible. However, creating digital pathology algorithms requires large volumes of training data, often on the order of thousands of histopathology slides. This becomes problematic for rare diseases, where imaging datasets of such size do not exist. This makes it impossible to train digital pathology models for these rare conditions. However, recent advances in generative deep learning models may provide a method for overcoming this lack of histology data for rare diseases. Pre-trained diffusion-based probabilistic models can be used to create photorealistic variations of existing images. In this study, we explored the potential of using a deep generative model created by OpenAI for the purpose of producing synthetic histopathology images, using chondrosarcoma as our rare tumor of interest. Methods: Our team compiled a dataset of 55 chondrosarcoma histolopathology images from the annotated records of Dr. Henry Jaffe, a pioneering authority in musculoskeletal pathology. We built a deep learning image-generation application in a Jupyter notebook environment, iterating upon OpenAI’s DALL-E application processing interface (API) with python programming language. Using the chondrosarcoma histology dataset and NVIDIA GPUs, we trained the deep learning application to generate multiple synthetic variations of each real chondrosarcoma image. Results: After several hours, the deep learning model successfully generated 1,000 images of chondrosarcoma from 55 original images. The synthetic histology images retained photorealistic quality and displayed characteristic cellular features of chondrosarcoma tumor tissue. Conclusions: Deep generative models may be useful in addressing issues of data scarcity in rare diseases, such as chondrosarcoma. For example, in situations where existing imaging data is insufficient for training diagnostic computer vision models, diffusion-based generative models could be applied to create training datasets. However, further exploration of ethical considerations and qualitative analyses of these generated data are needed.
Hypophosphatemia and thrombocytopenia: A retrospective chart review to identify markers for prediction of CRS and ICANS in CAR T-cell therapy.
Authors: Kenneth Barker, Aaron Bertolo, Cole Uhland, Shannon Koza, Emmanuel Katsanis, Muhammad Husnain
Journal: Journal of Clinical Oncology (2023)

e14524 Background: CAR T-cell therapy has transformed the treatment landscape of B cell malignancies. Adverse effects of CAR T include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We aimed to identify biomarkers predictive of CRS and ICANS post CAR T-cell therapy. Methods: A total of 34 patients (19 male and 15 female) with a median age of 68 years and ranging from 38 to 80 years old treated with CAR T-cells for B-cell malignancies at Banner University Medical Center/University of Arizona Cancer Center were evaluated. Phosphate (Ph), IL-6, ferritin, lactate dehydrogenase (LDH), and platelet count from each patient were recorded through retrospective chart review. A simple two-sample t test and ANOVA T-test were run to determine statistical significances by comparing the values of each parameter of interest between groups. Results: Of the 34 patients, 19 (56%) developed CRS without ICANS, 8 (24%) had both CRS and ICANS, and 7 (20%) developed neither. Of the 19 patients with CRS without ICANS, 13 (68%) had clinical hypophosphatemia compared to 0% of patients without CRS or CRS+ICANS. Average phosphate (Ph) nadir levels in the patients with CRS were significantly lower at 2.08 mg/dL compared to those in patients without CRS at 3.20 mg/dL ( P= .00007). Patients with CRS + ICANS had even lower Ph levels at 1.99 mg/dL when compared to patients without ( P= .004). Thrombocytopenia at time of infusion was significantly associated with the development of CRS with those patients having an average platelet count of 114 x 10 9 /L compared to 184 x 10 9 /L in patients without CRS or CRS+ICANS (P = .037). Interleukin-6 (IL-6) levels were elevated in all of patients who developed CRS with an average peak level of 102 pg/mL, however, an inadequate number of patients without CRS or CRS+ICANS were sampled thus precluding a statistical comparison in peak IL-6 levels between groups. Conclusions: Hypophosphatemia is associated with the development of both CRS alone and CRS+ICANS after CAR T cell therapy. A proposed mechanism is thought to be related to increased phosphate consumption by CAR T cell induced metabolic activity. Thrombocytopenia at the time of infusion was significantly associated with the development of CRS. Hypophosphatemia and thrombocytopenia show promise as markers for the prediction of CRS and ICANS in CAR T-Cell therapy.
Characterizing the tumor selectivity of oncolytic adenovirus ICVB-1042: Analysis of S-phase induction, viral replication, and cytolytic activity in human primary normal cell types.
Authors: Michael Pokrass, Peter Rosenthal, Joshua Messinger, Ruben Rodriguez, Heba Nowyhed
Journal: Journal of Clinical Oncology (2023)

e14503 Background: Adenoviral-based oncolytic virus (OV) therapeutics include mutations that enable activity in tumor cells and limit toxicity in normal cells. These tumor selectivity approaches often involve mutating viral E1A function or expression; however, such modifications allow viral activity in normal cells or limit anti-tumor potency. ICVB-1042 was engineered with dual modifications in E1A and E4orf6/7, resulting in superior tumor selectivity that does not compromise lytic potency in tumor cells. This improved tumor selective virus minimizes off-tumor activity and promotes robust tumor lysis. Methods: ICVB-1042 was compared to viruses with wildtype E1A and E4orf6/7 and a clinically tested virus with an E1A mutation (ICVB-2006). Viral function and killing were assessed in primary normal human renal (HRE) and bronchial (BrE) epithelial cells in the presence of the inhibitor palbociclib to pharmacologically block S-phase entry via host cell signaling. HRE and BrE were infected with virus and evaluated for indicators of viral toxicity in normal cells. Viral replication was quantified by droplet digital polymerase chain reaction (ddPCR); cell lysis was quantified by WST-1 assay. An S-phase induction assay was developed using an mCherry-Geminin reporter that allows imaging-based quantification of viral-dependent entry to S-phase. Viral activity in cells was compared with and without the CDK4/6 inhibitor using a viral-encoded fluorescent reporter to determine the requirement for host cell proliferation on viral function. Results: ICVB-1042 demonstrated superior protection in normal cells to comparator ICVB-2006 and viruses lacking tumor selectivity modifications. Palbociclib steeply reduced viral reporter gene expression (63-88% reduction), viral replication ( &gt; 10-fold reduction), and cytolytic activity of ICVB-1042, while non-selective viruses were unaffected by this treatment. Non-selective virus infection resulted in 3.3- to 6.1-fold higher levels of S-phase entry compared to ICVB-1042. ICVB-2006 infection resembled non-selective viruses at the level of S-phase induction (3.1- to 3.3-fold above ICVB-1042) and viral reporter gene expression was modestly inhibited by palbociclib (12-31% reduction). Conclusions: The improved tumor selectivity of ICVB-1042 results in protection of normal, non-proliferative cells from viral-mediated toxicity. The conventional approach of ICVB-2006 with a single E1A mutation leaves viral replication and cell death in normal human cells mostly intact. Together, these observations support that ICVB-1042 presents normal cell protection and reduced toxicity risks associated with OV therapy.